Targeting mitophagy in Parkinson's disease

Abstract

The genetics and pathophysiology of Parkinson’s disease (PD) strongly implicate mitochondria in disease aetiology. Elegant studies over the last two decades have elucidated complex molecular signaling governing the identification and removal of dysfunctional mitochondria from the cell, a process of mitochondrial quality control known as mitophagy. Mitochondrial deficits and specifically reduced mitophagy are evident in both sporadic and familial PD. Mendelian genetics attributes loss-of-function mutations in key mitophagy regulators PINK1 and Parkin to early-onset PD. Pharmacologically enhancing mitophagy and accelerating the removal of damaged mitochondria are of interest for developing a disease-modifying PD therapeutic. However, despite significant understanding of both PINK1-Parkin-dependent and -independent mitochondrial quality control pathways, the therapeutic potential of targeting mitophagy remains to be fully explored. Here, we provide a summary of the genetic evidence supporting the role for mitophagy failure as a pathogenic mechanism in PD. We assess the tractability of mitophagy pathways and prospects for drug discovery and consider intervention points for mitophagy enhancement. We explore the numerous hit molecules beginning to emerge from high-content/high-throughput screening as well as the biochemical and phenotypic assays that enabled these screens. The chemical and biological properties of these reference compounds suggest many could be used to interrogate and perturb mitochondrial biology to validate promising drug targets. Finally, we address key considerations and challenges in achieving preclinical proof-of-concept, including in vivo mitophagy reporter methodologies and disease models, as well as patient stratification and biomarker development for mitochondrial forms of the disease.

A Balanced Act: The Effects of GH–GHR–IGF1 Axis on Mitochondrial Function

“…To our knowledge, the most studied and understood mitophagy pathway is mediated by PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin (Narendra et al, 2008;Vives-Bauza et al, 2010), both of which have been linked to forms of Parkinson's disease (Kitada et al, 1998;Valente et al, 2004). The complicated mechanisms of canonical and non-canonical PINK1/parkinmediated mitophagy have been well summarized in previous reviews (Eiyama and Okamoto, 2015;Lazarou et al, 2015;Nguyen et al, 2016;Clark et al, 2020;Malpartida et al, 2020). Moreover, two main types of receptor-mediated mitophagy pathway have been classified as follows in brief: ubiquitinindependent mitophagy receptors, including BCL2-interacting protein 3 (BNIP3) (Quinsay et al, 2010), BCL2-interacting protein 3 like (NIX/BNIP3L) (Sandoval et al, 2008), FUN14 domain-containing 1 (FUNDC1) (Liu et al, 2012), BCL2-like 13 (BCL2L13) (Otsu et al, 2015), autophagy and beclin 1 regulator 1 (AMBRA1) (Strappazzon et al, 2015), FKBP prolyl isomerase 8 (FKBP8) (Bhujabal et al, 2017), prohibitin 2 (PHB2) (Wei et al, 2017), and NLR family member X1 (NLRX1) (Zhang et al, 2019); lipid-mediated mitophagy receptors, including ceramide (Sentelle et al, 2012) and cardiolipin (Li et al, 2015).…”

Protein clearance strategies for disease intervention

“…These findings led to the discovery and patent of US-2016/0160205A1 and WO-2018/023029 as small molecule activators of parkin. Currently, there are no in vitro or in vivo data available regarding these molecules (Clark et al 2020 ; Miller and Muqit 2019 ).…”

Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches

“…Mitochondrial homeostasis is important for the survival of healthy cells. Indeed, mitochondrial dysfunction has been linked to several diseases including neurodegenerative disorders such as Parkinson's disease (PD) [1][2][3][4][5]. PD is a chronic, progressive neurodegenerative disease that has been linked mechanistically and genetically to alterations in mitochondrial homeostasis [1,[6][7][8].…”